Liquid metal ammino sulfa compounds



Patented Feb. 24, 1953 UNITED STATES PATENT OFFICE LIQUID METAL AMMINO SULFA COMPOUNDS Sam Rosenzweig and Walter M. Fuchs, New York, N. Y.; said Fuchs assignor to said Rosenzweig No Drawing.

Original application June 3, 1947,

Serial No. 752,293. Divided and this application November 7, 1950, Serial No. 194,723

3 Claims.

wherein X represents a large variety of organic radicals of varying degrees of complexity. In the constant search for agents of improved utility and higher bactericidal activity, a wide variety of derivatives of the sulfa compounds have been prepared. It is known that one of the hydrogen atoms bonded to the amide nitrogen atom of sulfanilamide (usually referred to as the N position) is acidic in character and can be replaced with a metal to form a metal salt. The second hydrogen atom is not replaceable by a metal under ordinary conditions. The single hydrogen atom bonded to the N nitrogen atom in the compounds of Formula I can likewise be replaced with metals to form metal salts. In this manner, alkali metal salts, such as the sodium and potassium salts, as well as heavy metal salts, such as the iron, gold, copper and silver salts of a number of sulfa compounds have been prepared. The hydrogen atoms bonded to the amino nitrogen atom in the position para to the sulfoxy group (usually referred to as the N position) are apparently incapable of being replaced by metals under ordinary conditions, the -NH2 group showing most of the characteristics of an aryl amine.

The N metal salts of sulfa compounds just referred to are of interest in that they contain within the same molecule a sulfa compound and a heavy metal, both of which with few exceptions, have definite physiological effects. Many soluble salts of certain of the heavy metals, particularly of silver, copper, zinc, mercury and gold, are known to be definitely bactericidal or fungicidal, but they are frequently too toxic, to be of value. The sulfa compounds alone, on the other hand, are generally considered to be bacteriostatic rather than bactericidal. It was thought that the combination of a heavy metal and a sulfa compound in the same molecule might prove beneficial. Unfortunately, however, the heavy metal salts of sulfa compounds are highly insoluble in water and have exhibited little or no practical utility due, in part, to the lack of methods suitable for application of the substances.

It has now been found that compounds formed by replacing an N, or amido, hydrogen atom in a sulfa compound with a heavy metal and having the formula Marisol-Oneal)- wherein M represents a heavy metal, a: represents the valence of the heavy metal and R represents hydrogen or an organic radical, may be reacted with amines or ammonia to form new complex compounds having the formula III wherein M and R have the values given, Am represents ammonia or an amine and :c is an integer equal to the valence of the heavy metal. These compounds are herein referred to as metal di-ammino sulfa compounds.

A preferred embodiment of the invention contemplates new compounds having the formula wherein M is a heavy metal from the group silver, mercury, zinc, palladium, nickel and copper, Am is a basic nitrogen compound from the group ammonia, primary amines containing the group -CH2NHCH2 and heterocyclic amines containing a hetero amino nitrogen atom, R is from' the group hydrogen and heterocyclic radicals containing a hetero nitrogen atom and :c is an integer equal to the valence of the heavy metal.

Most of the new complex compounds are crystalline solids from which the ammonia or amine is expelled by heating to leave the metal salt of the sulfa compound having the formula Some of the compounds tend to occur as somewhat tacky solids.

The compounds are decomposed very slowly by water with the formation of the free amine and the metal salt of the sulfa compound. They are decomposed somewhat more rapidly by very dilute aqueous mineral acids with the formation of the metal salt of the sulfa compound and a mineral acid salt of the amine orammonia. In the presence of sufficient strong mineral acid, the decomposition proceeds further with the formation of the free sulfa compound and the mineral acid salt of the metal. The new complex compounds are generally insoluble in water and in most organic liquids. They are, however, soluble in many liquid amines and mixtures thereof, and in aqueous solution of amines or of ammonia and are stable over long periods of timein such solutions. Aqueous solutions .of .hydroxyalkyl amines, such as aminoethanol, aminopropanol, aminobutanol and diethanol amine, particularly the monohydroxyalkyl amines, are well suited as solvents for the new compounds. The complex compounds have a faint odor of amine orammonia but are stable over long'periods oftime at ordinary temperatures, particularly when 'in closed containers protected from excessive atmospheric moisture.

The complex compounds described here for the first time find utility in the field of bactericides, fungicides, "germicides and antiseptics. They may be incorporated in high concentrations in the solvents mentioned to provide solutions of high bactericidal value.

In certain uses of the compounds, advantage is taken of their property of reverting to the metal salt of the sulfa compound when heated. Thus, fibrous articles, such as canvas, spongesand the like, andeven only slightly porous articles such-"as bristles, are soaked thoroughly in'a solution of one or a mixture of the complex compounds'and then dried and heated. The amine-or ammonia is thus volatilized leaving the highly insoluble metal salt of th sulfa compound evenly distributed throughout the interstices of the article in a form difficult to remove by washing. Substantially the same result is accomplished by treating the soaked article with-a dilute aqueous solution of a mineral acid in amount'sufiicient to combine with the amine or ammonia, but insufficient to decompose the metal salt of the sulfa compound. Articles so treated are highlyselfsterilizing.

Amines which can be used in preparing compounds of the invention include monomethylamine, monoethyl amine, mono-n-propyl amine, mono-iso-propyl amine, ethylene diamine, benzyl amine,.monoethanol amine, morpholine, diethanol amine, ephedrine (methyl-(a-methyl bhydroxy-b-phenyl-ethyl) amine) neosynephrine (methyl b-3 -hydroxyphenyl-b -hydroxy-ethyl amine), pyridine and quinoline. Heterocyclic radicals containin a hetero nitrogen atom, represented by R in the Formula IV, include the pyridyl, thiazolyl, diazyl, methyldiazyl and dimethyldiazyl radicals occurring in sulfapyridine, sulfathiazole, sulfadiazine, sulfamerazine, 'and sulfamethazine, respectively, as well as many others.

The metal salts of sulfa compounds used as intermediates in preparing the complex compounds of the invention can be prepared readily by dissolving the sulfa compound in an equivalent amount of an aqueous alkali, such as sodium hydroxide, and mixing the solution with about an equivalent amount of an aqueous solution of 'a water-soluble salt of the metal. The metal salts of the sulfa compounds are formed as insoluble precipitates, some of which are colored, depending upon the metal involved. They can be recovered readily in good yield and in a state of high purity by filtering the mixture and washing the salt with water. The reaction is preferably carried out at apH of about 5,'although the compounds may be formed at a pH somewhat higher or lower than this but often with considerable sacrificein yield. Representative examples are iven hereinafter illustrating the preparation of a number of these intermediate metal salts of sulfa compounds.

The complex compounds of the invention may .be prepared in a. number of ways, one convenient way .being by .dissolvin the metal salt of the sulfa .compound in an appropriate anhydrous liquid .amine. Upon evaporation of the excess amine,'the complex compound remains. Alternatively, th solution of the metal salt of the sulfa compound in the amine may be diluted by the gradual addition of a liquid inert under the reaction conditions and miscible with the amine, such as toluene, xylene, carbon tetrachloride, chloroform, and the like. The complex compound is precipitated by this procedure and after recovery by filtering is washed thoroughly with additional portions of the inert liquid and-then dried. In this way, the complex compounds are obtained in high yield and in a state of high purity. Complex compounds containing ammonia rather than an amine may be prepared in a similar manner using liquid ammonia and allowing the excess to evaporate.

In some instances, complete solution of the metal salt of the sulfa compound in the amount of amine used may not be obtained, the complex compound beginning to separate as crystals before all the metal salt of the sulfa compound has dissolved. In other instances, i. e., when neither the salt of the sulfa compound or the complexcompound are appreciably soluble in the particular amine employed, the progress of the reaction is apparent only by a change in the appearance of thesolid phase. The procedure described is, however,.applicable in such cases.

.Metal .di-ammino sulfa compounds contemplated by the invention include, among many others, the following:

Silver 'di-ammono sulfanilamide Silver di-ammono sulfadiazine Silver di-ammono sulfathiazole Silver di-ammono sulfapyridine Silver di-morpholinammino sulfapyridine Silver di-me'thylammino sulfadiazine Silver di-morpholinammino sulfanilamide Silver di-ethylammino sulfadiazine Silver di-morpholinammino sulfadiazine Silver di-morpholinammino sulfathiazole Silver di-ethylenediammino sulfadiazine Silver di-benzylammino sulfadiazine Silver di-methyl-(b 3 hydroxyphenyl b hy droXy-ethyl) ammino sulfadiazine Silver di-monoethanolammino sulfathiazole Cupric di-ethylammino sulfadiazine Cupric di-butylammino sulfapyridine Cupric di-n-propylammino sulfanilamide Cupric di-ethylenediammino sulfapyridine Cupric di-morpholinammino sulfathiazole Cupric di-ethanolammino sulfathiazole Cupric di-diethanolammino sulfadiazine Cupric di-benzylammino sulfathiazole Mercuric di-ethylammino sulfapyridine Mercuric di-butylammino sulfamerazine' Zinc di-morpholinammino sulfathiazole l Palladium di-isoprop-ylammino sulfamerazine Palladium di-morpholinammino sulfathiazole Palladium di-ethylammino sulfamerazine Palladium di-diethanolammino sulfadiazine Nickel di-morpholinammino sulfathiazole an appropriate metal salt. Metal salts used in the several preparations included: CuSO4.5HzO, Hg(NO )2.H2O, Ni(NOs)2.I-I20, PdClz, 211012 and AgNOs. The pH of the solution was in ;each case adjusted to about with nitric acid. The metal salt of the sulfa compound formed as a precipitate in each case and was recovered by filtering, washing with water and drying. Each of the dried salts was analyzed for metal content without further purification. In the accompanying Table I there are given for each determination the sulfa compound used, the metal salt used, the formula, yield and color of the compound formed, and the theoretical and actual per cent of metal in the compound.

Table I Yield based Percent Metal sulfa Empirical Formula on Amount pound Used Metal Salt Used of Compound of Sulfa Color Formed Co%g:1nd Theory Found sulfathiazole... CuSO4.5HqO (CnHsNsOzSglzCll 100 bordeaux rcd 11. l 10. 6 D0 Hg(NO3)z.H2O ((vHaNa -l SzlzHg 100 white 28. 3 27. 8 Ni(NOa)1.HO (OnHgNgOzSzliNl 91 light green. 10.3 10. 2 PdC1; (CgHgNzOgSglgPd 83 orange brown 17. 3 17.-() ZnCl1 (CsHsNgOgSzlzZlL, 100 11.4 11.2 D0 AgNO; 'C9H5N301s1Ag. 100 (l 29. 8 30. 2 Sulfanilamide... AgNO; CaH1N20zSAg.. 100 38. 5 39. 1 Sulfadiazine. AgNoz C1oHqN40zSAg 100 30.0 29. 7 Su1fapyridine AgNOl C11H1flN302s g--- 100 30. 1 29.8

Nickel di-benzylammino sulfanilamide Nickel di-methyl -(b -3- hydroxyphenyl b hy droxy-ethyDammino sulfapyridine Nickel di-pyridinammino sulfadiazine Nickel di-methyl-(a-methyl-b-hydroxy -bphenyl-ethyl) ammino sulfathiazole The complex compounds can be analyzed by a titration method substantially as follows: A" sample of the product of convenient size is stirred with 100 milliliters of water, warmed gently and titrated with standard hydrochloric acid solution. The end point may be determined using an indicator, such as methyl orange, or electrometrically. The latter is advisable in the case of compounds of certain metals, e. g., copper, mercury and palladium, which tend to form colored mixtures which obscure the color change of an. indicator. The use of a slight excess of acid followed by back-titration with standard alkali hastens the process. necessary to form the hydrochloride of the amine present in the compound. The mixture is then acidulated strongly with concentrated hydrochloric acid which decomposes the metal salt of the sulfa compound, and the metal in the solution is then determined in any convenient way. In the case of silver compounds, acidulation with an excess of hydrochloric acid precipitates silveras the chloride which can be recovered by filtering, washing thoroughly with acetone to remove sulfa compound and then drying and weighing.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

EXAMPLE 1 A number of metal salts of sulfa compoundwere prepared as follows:

One equivalent weight of an appropriate sulfa'70 compound was stirred with an aqueous solution containing one equivalent weight of sodium hydroxide until dissolved. This solution. was then added slowl-ywith stirring to an aqueous solution containing about one equivalent weight of 75.

The acid consumed is that 50 EXAMPLE 2 I EXAMPLE 3 Two grams of silver sulfadiazine were mixed with five grams of methyl-(b-3-hydroxyphenylb-hydroxy-ethyl) -amine and 20 milliliters of glacial acetic acid was added. The mixture was kept at room temperature for two hours with frequent stirring. The solid phase at first became somewhat soft but gradually changed to a fine powder. The mixture was filtered through a fritted glass filter and the solid product washed several times with small portions of glacial acetic acid and then with chloroform. The product after drying in vacuo over alkali consisted of 2.5

grams of silver di-methyl-(b-3-hydroxy-phenylb-hydroxy-ethyl) ammino sulfadiazine.

The compound is insoluble in water but easily soluble in monoethanol amine, the solution re maining clear upon dilution with water.

Anal.:

Calcd for C28H330sNeSAg2 CsHaOsNHCHa, 48.0. Found: Ag, 15.9; CsHsOaNHCI-Ia, 48.0.

EXAIWPLE 4 Two grams of silver sulfathiazole and 10 grams of monoethanol amine were stirred together until all of the solid material had dissolved. Silver di-monoethanolammino sulfathiazole was precipitated from the mixture by the addition of an i7 excess of chloroform, the mixture flltereds and the solid washed thoroughly with chloroform and dried. The dryproduct was'awhite somewhat waxysolid soluble in aqueous ethanolamine, but insoluble in water.

Anal:

Calcd for C13H22O4N5S2Ag: Ag, 2223.

Found: Ag, 22.0.

EXAMPLE "Two grams of silver sulfadiazine'was dissolved in grams of ethylamine. A yellow solution was formed. .The ethylamine was allowed to evaporate and'there remained 2.6 grams of a yellow wherein R":represents the thiazolyl-Z radical. This basic gold salt of'sulfathiazole can then be reacted with an amine to forma compound which still contains an hydroxylgroup and which also contains three molecules of amine. This latter compound has an analysis corresponding to the formula wherein Am"represents a molecule of an amine and R has the value given.

EXAMPLE 7 solid which u on dr in in vacuo'became white.

p y g A solution was prepared by dlSSOlVll'lg two grams Anal: of chloroauric acid AllC13.HC1.4I-I2O, in milli- C d for mH s e z I -1; s litersof water and this solution was stirred slowly 7 into a solution of 3.9 grams of sulfathiazole in 41 Found: -7; 2 5 2.-2 20 milliliters of N/2 sodium hydroxide. The brown, EXAMPLE amorphous precipitate which formed was filtered V V p on a fritted glass filter and Washed with water A number of metal 'f sulfa compounds until the washings gave .a negative reaction for were prepared substamlany as by the methodspf halogen. The product,'after drying at 100 C. and ga i to 5 ja i then in vacuo, weighed 3.8 grams. Analysis of e compoun prepare e empmca the product without further purification indicated formula of each and the theoreticaland deterit to bea ba sic gold salt of sulfathiazole. mined percentages of metal and of amine in each are given in the accompanying Table II. The Anal. compounds prepared in Examples 2 to 5, .lnclu- Calcd for C1aI-I17NeO5S4Au: Au, 27.2. sive, are included by wayof comparison. Found: Au, 26.8.

Table. II

Percent Metal Percent'Amlne Compound Empirical Formula .Color Thcor. Found Theor. 'Found l Silver dimorpholinammino .C lH; N 04SAg "white 23.8 22.9 38.4 39.0

sulfanilamidc. 2 'Silver di-morpholinammino CmH N5O4SAg do T20L3 20.5 32.7 32.0

sulfadiazine. 3 'Silver dc-morpholinammino CitHggN OfiAg .do 120.4 "20.6 3218 32.0

sulfapyridine. 4 Silver di-morpholinammino CUHIBNBOASJAg .do 20.1 20.3 32.5 31.7

sulfathiazole. 5 Copper di-morpholinam- 'CiQH NQOQSlOuMv red 3.5 8.2 .2313 22.8

mino sulfathiazole. Nickel di-morpholinammino CuH34N5O5s4Ni"... light green. 7.9 7.7 23.4 23.0

sulfathiazole. 7 Palladium di-morpholinam- C2LH:(HEO5S4PG.-.- orange brown. 13.5 14.0 21.1.

mino sulfathiazole. 8 Zinc di-morpholinammino C; H; HO@S Zn white m- '8Z7 8.7 2812 23.6

sulfathiazole. 9 Silver'di-animono sulfadia- 'C 'H 'N5O SAg .do 27.6 27.2 8; 7 9.5

"Z1118. 10 Silvgr di-ethylammino sul- GuHzrNsOzSAg ..do A "-24.1 -23.7 20.1 23.5

3. lr'lZlTlB. ll Silver di-cthylcnediammino '(l liuN o sAg do 122.6 322.2 25.2 25.5

V sulfadiazine. l2 Silverdi-benzylammino sulognnmmsa -.do 18.8 18.4 37.5 38.1

.iadiazine. 13 Silver di-methyl-(b-3hydro- 'xyphenyl-b-hydroxyethyl) ammino' su'Jfadia,

zinc G,sH,';N,o,sA dc 15.6 15.9 48.0 48.0 14 Silver di-mono-ethanolamminosuliathiazolo .Ci:HnN OiS;Ag. do 22.3 22.0 25.2

Although the present invention is particularly concerned with compounds having the Formula EXAMPLE 8 IV given previously, it also contemplates other complex compounds closely allied thereto, but comprising 'a'number of molecules'of amine in each molecule of the complex compound different from two. The invention also contemplates certain complex compounds which maybe described'as basic in character in that theyiapparently contain an hydroxyl radical in-the molecule. Thus auric chloride canbe. reacted with sulfathiazole in the form of its alkali metal salt to produce a compoundhaving .anzana'lysis corresponding;to the formula Two grams of the basic gold salt of sulfathiazole,, prepared as in Example 7, was dissolved in 20 grams ofmorpholine. The dark-colored, clear solution which formed waspoured with stirrin into 200 milliliters of benzene. A precipitate formed which was at first somewhat tacky but which hardened slowly uponstanding. The precipitatewas washed with benzene by decantation and finallyv filtered and dried. The dried product weighed 2.4 grams. Analysis without further puriflcationindicated the :product to be a complexrcompound comprisinga basic gold salt of suliathiazo'le: and three molecules of morpholine.

9 Anal.

Calcd for C30H44N9O3S4Al1: Au, 20.0; morpholine, 26.5. Found: Au, 19.5; morpholine, 26.8.

We claim: 1. A liquid product comprising an amine and a compound having the formula mama-rtsw-O-rrm wherein M is a heavy metal from the group silver, mercury, zinc, palladium, nickel and copper, Am is a basic organic nitrogen compound from the group consisting of ammonia, primary alkyl amines, primary hydroxyalkyl amines, primary aminoalkyl amines, primary araikyl amines, secondary hydroxyaralkyl alkyl amines and monocyclic heterocyclic basic nitrogen compounds devoid of hetero atoms other than nitrogen and oxygen, R is from the group hydrogen and heterocyclic radicals containing a hetero nitrogen atom and a: is an integer equal to the valence of the heavy metal the amine being from the same group as the basic organic nitrogen compound.

2. A liquid product as claimed in claim 1 wherein the amine is a monoalkanol amine.

3. A liquid product as claimed in claim 1 wherein the amine is monoethanol amine.

SAM ROSENZWEIG. WALTER M. FUCHS.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,361,624 Hamilton Oct. 31, 1944 2,429,404 Dixon Oct. 21, 1947 2,442,602 Hubner June 1, 1948 

1. A LIQUID PRODUCT COMPRISING AN AMINE AND A COMPOUND HAVING THE FORMULA 